Obstructive sleep apnea (OSA) results in cardiac dysfunction and vascular endothelium injury. Chronic intermittent hypoxia (CIH), the main characteristic of OSAS, is considered to be mainly responsible for cardiovascular system impairment. This study is aimed to evaluate the role of endothelin-1(ET-1) system in coronary injury and cardiac dysfunction in CIH rats. In our study, Sprague-Dawley rats were exposed to CIH (FiO2 9% for 1.5 min, repeated every 3 min for 8 h/d, 7 days/week for 3 weeks). After 3 weeks, the left ventricular developed pressure (LVDP) and coronary resistance (CR) were measured with the langendorff mode in isolated hearts. Meanwhile, expressions of ET-1 and ET receptors were detected by immunohistochemical and western blot, histological changes were also observed to determine effects of CIH on coronary endothelial cells. Results suggested that decreased LVDP level combined with augmented coronary resistance was exist in CIH rats. CIH could induce endothelial injury and endothelium-dependent vasodilatation dysfunction in the coronary arteries. Furthermore, ET-1 and ETA receptor expressions in coronary vessels were increased after CIH exposure, whereas ETB receptors expression was decreased. Coronary contractile response to ET-1 in both normoxia and CIH rats was inhibited by ETA receptor antagonist BQ123. However, ETB receptor antagonist BQ788 enhanced ET-1-induced contractile in normoxia group, but had no significant effects on CIH group. These results indicate that CIH-induced cardiac dysfunction may be associated with coronary injury. ET-1 plays an important role in coronary pathogenesis of CIH through ETA receptor by mediating a potent vasoconstrictor response. Moreover, decreased ETB receptor expression that leads to endothelium-dependent vasodilatation decline, might be also participated in coronary and cardiac dysfunction.

Abstract We have previously reported that 4 weeks of intermittent hypoxia (IH) exposure, mimicking the hypoxic stress of obstructive sleep apnea, produces compensatory increases in left ventricular (LV) contractility in lean C57BL/6J mice. In this study we compared the effects of 4 weeks IH to 4 weeks of sustained hypoxia (SH) on LV function and cardiac glycolysis in lean C57BL/6J mice and obese ob/ob mice at 10-12 weeks of age. The four exposure conditions were IH (nadir O2 [5-6%] at 60 cycles/h during the 12 h light period), SH (24 h inspired O2 [10%]), and control groups of intermittent air (IA) or room air. Cardiac function was assessed under isoflurane anesthesia (1-2%) by echocardiography and pressure-volume loop analysis and myocardial glycolytic rates were determined ex vivo using radiolabeled (3)H-glucose. Lean mice exposed to IH exhibited increases in contractile parameters which were associated with elevated glycolytic rates (3.4 vs. 5.7 μg/μL·g; P < 0.05). Ob/ob mice did not show any improvements in contractility after IH. Moreover, cardiac glycolytic rates and LV systolic and diastolic function did not differ from IA ob/ob controls. Following SH exposure, lean mice exhibited increased contractility and glycolytic rates (3.8 vs. 5.7 μg/μL·g; P < 0.05), however, LV lumen dimensions were reduced. In contrast, ob/ob mice exposed to SH show compromised systolic and diastolic function associated with unchanging glycolytic rates. These findings demonstrate that, in a murine model of obesity, an inability to increase glycolysis is associated with an absence of an adaptive cardiac response to IH and marked systolic and diastolic dysfunction in response to SH.

Sympathoexcitation contributes to the progression of heart failure. Activation of brain angiotensin II type 1 receptors (AT1R) causes central sympathoexcitation. Thus, we assessed the hypothesis that the increase in circulating angiotensin II comparable to that reported in heart failure model affects cardiac function through the central sympathoexcitation via activating AT1R in the brain. In Sprague-Dawley rats, the subcutaneous infusion of angiotensin II for 14 days increased the circulating angiotensin II level comparable to that reported in heart failure model rats after myocardial infarction. In comparison with the control, angiotensin II infusion increased 24 hours urinary norepinephrine excretion, and systolic blood pressure. Angiotensin II infusion hypertrophied left ventricular (LV) without changing chamber dimensions while increased end-diastolic pressure. The LV pressure -: volume relationship indicated that angiotensin II did not impact on the end-systolic elastance, whereas significantly increased end-diastolic elastance. Chronic intracerebroventricular infusion of AT1R blocker, losartan, attenuated these angiotensin II-induced changes. In conclusion, circulating angiotensin II in heart failure is capable of inducing sympathoexcitation via in part AT1R in the brain, subsequently leading to LV diastolic dysfunction.

Duchenne muscular dystrophy (DMD), caused by absence of the protein dystrophin, is a common, degenerative muscle disease affecting 1:5000 males worldwide. With recent advances in respiratory care, cardiac dysfunction now accounts for 50% of mortality in DMD. Recently, we demonstrated that simvastatin substantially improved skeletal muscle health and function in mdx (DMD) mice. Given the known cardiovascular benefits ascribed to statins, the aim of this study was to evaluate the efficacy of simvastatin on cardiac function in mdx mice. Remarkably, in 12-month old mdx mice, simvastatin reversed diastolic dysfunction to normal after short-term treatment (8 weeks), as measured by echocardiography in animals anesthetized with isoflurane and administered dobutamine to maintain a physiological heart rate. This improvement in diastolic function was accompanied by increased phospholamban phosphorylation in simvastatin-treated mice. Echocardiography measurements during long-term treatment, from 6 months up to 18 months of age, showed that simvastatin significantly improved in vivo cardiac function compared to untreated mdx mice, and prevented fibrosis in these very old animals. Cardiac dysfunction in DMD is also characterized by decreased heart rate variability (HRV), which indicates autonomic function dysregulation. Therefore, we measured cardiac ECG and demonstrated that short-term simvastatin treatment significantly increased heart rate variability (HRV) in 14-month-old conscious mdx mice, which was reversed by atropine. This finding suggests that enhanced parasympathetic function is likely responsible for the improved HRV mediated by simvastatin. Together, these findings indicate that simvastatin markedly improves cardiac health and function in dystrophic mice, and therefore may provide a novel approach for treating cardiomyopathy in DMD.

Cardiac power, the product of aortic flow and blood pressure, appears to be a fundamental cardiovascular parameter. The simplified version named cardiac power output (CPO), calculated as the product of cardiac output (CO) in L/min and mean arterial pressure (MAP) in mmHg divided by 451, has shown great ability to predict outcome in a broad spectrum of cardiac disease. Beat-by-beat evaluation of cardiac power (PWR) therefore appears to be a possibly valuable addition when monitoring circulatory unstable patients, providing parameters of overall cardiovascular function. We have developed a minimally invasive system for cardiac power measurement, and aimed in this study to compare this system to an invasive method (ttPWR). Seven male anesthetized farm pigs were included. A laptop with in-house software gathered audio from Doppler signals of aortic flow and blood pressure from the patient monitor to continuously calculate and display a minimally invasive cardiac power trace (uPWR). The time integral per cardiac cycle (uPWR-integral) represents cardiac work, and was compared to the invasive counterpart (ttPWR-integral). Signals were obtained at baseline, during mechanically manipulated preload and afterload, before and after induced global ischemic left ventricular dysfunction. We found that the uPWR-integral overestimated compared to the ttPWR-integral by about 10% (P < 0.001) in both normal hearts and during ventricular dysfunction. Bland-Altman limits of agreement were at +0.060 and -0.054 J, without increasing spread over the range. In conclusion we find that the minimally invasive system follows its invasive counterpart, and is ready for clinical research of cardiac power parameters.

Duchenne muscular dystrophy (DMD) is a progressive striated muscle disease that is characterized by skeletal muscle weakness with progressive respiratory and cardiac failure. Together respiratory and cardiac disease account for the majority of mortality in the DMD patient population. However, little is known regarding the effects of respiratory dysfunction on the dystrophic heart. The studies described here examine the effects of acute hypoxia on cardiac function. These studies demonstrate, for the first time, that a mouse model of DMD displays significant mortality following acute exposure to hypoxia. This mortality is characterized by a steady decline in systolic function. Retrospective analysis reveals that significant decreases in diastolic dysfunction, especially in the right ventricle, precede the decline in systolic pressure. The initial hemodynamic response to acute hypoxia in the mouse is similar to that observed in larger species, with significant increases in right ventricular afterload and decreases in left ventricular preload being observed. Significant increases in heart rate and contractility suggest hypoxia-induced activation of the sympathetic nervous system. These studies provide evidence that while hypoxia presents significant hemodynamic challenges to the dystrophic right ventricle, global cardiac dysfunction precedes hypoxia-induced mortality in the dystrophic heart. These findings are clinically relevant as the respiratory insufficiency evident in patients with DMD results in significant bouts of hypoxia. The results of these studies indicate that hypoxia may contribute to the acceleration of the heart disease in DMD patients. Importantly, hypoxia can be avoided through the use of ventilatory support.

Supplemental oxygen (O2 ) therapy in preterm infants impairs lung development, but the impact of O2 on long-term systemic vascular structure and function has not been well-explored. The present study tested the hypothesis that neonatal O2 therapy induces long-term structural and functional alterations in the systemic vasculature, resulting in vascular stiffness observed in children and young adults born preterm. Newborn Sprague-Dawley rats were exposed to normoxia (21% O2 ) or hyperoxia (85% O2 ) for 1 and 3 weeks. A subgroup exposed to 3 weeks hyperoxia was recovered in normoxia for an additional 3 weeks. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound and pressure myography. Aorta remodeling was assessed by collagen deposition and expression. Left ventricular (LV) function was assessed by echocardiography. We found that neonatal hyperoxia exposure increased vascular stiffness at 3 weeks, which persisted after normoxic recovery at 6 weeks of age. These findings were accompanied by increased PWV, aortic remodeling, and altered LV function as evidenced by decreased ejection fraction, cardiac output, and stroke volume. Importantly, these functional changes were associated with increased collagen deposition in the aorta. Together, these findings demonstrate that neonatal hyperoxia induces early and sustained biomechanical alterations in the systemic vasculature and impairs LV function. Early identification of preterm infants who are at risk of developing systemic vascular dysfunction will be crucial in developing targeted prevention strategies that may improve the long-term cardiovascular outcomes in this vulnerable population.

Long ncRNAs (lncRNAs) have been shown to play a biological and physiological role in various tissues including the heart. We and others have previously established that the lncRNA Oip5os1 (1700020I14Rik, OIP5-AS1, Cyrano) is enriched in striated muscles, and its deletion in mice leads to defects in both skeletal and cardiac muscle function. In the present study, we investigated the impact of global Oip5os1 deletion on cardiac function in the setting of streptozotocin (STZ)-induced diabetes. Specifically, we studied male WT and KO mice with or without diabetes for 24 weeks, and phenotyped animals for metabolic and cardiac endpoints. Independent of genotype, diabetes was associated with left ventricular diastolic dysfunction based on a fall in E'/A' ratio. Deletion of Oip5os1 in a setting of diabetes had no significant impact on ventricular function or ventricular weight, but was associated with left atrial dysfunction (reduced fractional shortening) and myopathy which was associated with anesthesia intolerance and premature death in the majority of KO mice tested during cardiac functional assessment. This atrial phenotype was not observed in WT diabetic mice. The most striking molecular difference was a reduction in the metabolic regulator ERRalpha in the atria of KO mice compared with WT mice. There was also a trend for a reduction in Serca2a. These findings highlight Oip5os1 as a gene of interest in aspects of atrial function in the setting of diabetes, highlighting an additional functional role for this lncRNA in cardiac pathological settings.

Titin-dependent stiffening of cardiomyocytes is a significant contributor to left ventricular (LV) diastolic dysfunction in heart failure with preserved LV ejection fraction (HFpEF). Small heat shock proteins (HSPs), such as HSPB5 and HSPB1, protect titin and administration of HSPB5 in vitro lowers cardiomyocyte stiffness in pressure-overload hypertrophy. In humans, oral treatment with geranylgeranylacetone (GGA) increases myocardial HSP expression, but the functional implications are unknown. Our objective was to investigate whether oral GGA treatment lowers cardiomyocyte stiffness and attenuates LV diastolic dysfunction in a rat model of the cardiometabolic syndrome. Twenty-one-week-old male lean (n = 10) and obese (n = 20) ZSF1 rats were studied, and obese rats were randomized to receive GGA (200 mg/kg/day) or vehicle by oral gavage for 4 weeks. Echocardiography and cardiac catheterization were performed before sacrifice at 25 weeks of age. Titin-based stiffness (Fpassive ) was determined by force measurements in relaxing solution with 100 nM [Ca2+ ] in permeabilized cardiomyocytes at sarcomere lengths (SL) ranging from 1.8 to 2.4 μm. In obese ZSF1 rats, GGA reduced isovolumic relaxation time of the LV without affecting blood pressure, EF or LV weight. In cardiomyocytes, GGA increased myofilament-bound HSPB5 and HSPB1 expression. Vehicle-treated obese rats exhibited higher cardiomyocyte stiffness at all SLs compared to lean rats, while GGA reduced stiffness at SL 2.0 μm. In obese ZSF1 rats, oral GGA treatment improves cardiomyocyte stiffness by increasing myofilament-bound HSPB1 and HSPB5. GGA could represent a potential novel therapy for the early stage of diastolic dysfunction in the cardiometabolic syndrome.

Although extensively used for the study of left ventricular function, limited experience exists with the isolated heart model in the evaluation of right ventricular (RV) function. In particular, no published experience exists with this tool in sugen/hypoxia-induced pulmonary hypertension (SuHx-PH), a frequently used model of severe and progressive PH We sought to characterize markers of RV contractile and diastolic function in SuHx-PH and to establish their relationship with markers of maladaptive RV remodeling. Hearts were excised from anesthetized Sprague Dawley rats with or without SuHx-PH and perfused via the aorta using a Langendorff preparation. We explored the Frank-Starling relationship of RV function (RV developed pressure, dP/dtmax, and dP/dtmin; all normalized to RV mass) by increasing RV end-diastolic pressure (RVEDP) from 0 to 40 mmHg. Functional studies were complemented by quantification of RV pro-apoptotic signaling (bcl2/bax), procontractile signaling (apelin), and stress response signaling (p38MAPK activation). Pearson's correlation analysis was performed for functional and biochemical parameters. SuHx-RVs exhibited severe RV dysfunction with marked hypertrophy and decreased echocardiographic cardiac output. For any given RVEDP, SuHx-RVs demonstrated less developed pressure and lower dP/dtmax, as well as less pronounced dP/dtmin, suggestive of decreased contractile and diastolic function. SuHx-RVs exhibited decreased bcl2/bax ratios, apelin expression, and p38MAPK activation. Bcl2/bax and apelin RNA abundance correlated positively with RV developed pressure and dP/dtmax and negatively with dP/dtmin p38MAPK activation correlated positively with RV developed pressure. We conclude that SuHx-RVs exhibit severe contractile and diastolic dysfunction. Increased pro-apoptotic signaling and attenuated procontractile and stress response signaling may contribute to these functional alterations.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.

Victims of chlorine (Cl2) inhalation that die demonstrate significant cardiac pathology. However, a gap exists in the understanding of Cl2-induced cardiac dysfunction. This study was performed to characterize cardiac dysfunction occurring after Cl2 exposure in rats at concentrations mimicking accidental human exposures (in the range of 500 or 600 ppm for 30 min). Inhalation of 500 ppm Cl2 for 30 min resulted in increased lactate in the coronary sinus of the rats suggesting an increase in anaerobic metabolism by the heart. There was also an attenuation of myocardial contractile force in an ex vivo (Langendorff technique) retrograde perfused heart preparation. After 20 h of return to room air, Cl2 exposure at 500 ppm was associated with a reduction in systolic and diastolic blood pressure as well echocardiographic/Doppler evidence of significant left ventricular systolic and diastolic dysfunction. Cl2 exposure at 600 ppm (30 min) was associated with biventricular failure (observed at 2 h after exposure) and death. Cardiac mechanical dysfunction persisted despite increasing the inspired oxygen fraction concentration in Cl2-exposed rats (500 ppm) to ameliorate hypoxia that occurs after Cl2 inhalation. Similarly ex vivo cardiac mechanical dysfunction was reproduced by sole exposure to chloramine (a potential circulating Cl2 reactant product). These results suggest an independent and distinctive role of Cl2 (and its reactants) in inducing cardiac toxicity and potentially contributing to mortality.

We sought to explore whether fetal hypoxia exposure, an insult of placental insufficiency, is associated with left ventricular dysfunction and increased aortic stiffness at early postnatal ages.

Fluid retention is the main reason for the high hospitalization rate among patients with chronic heart failure (CHF). Given the lack of knowledge about fluid intake regulation and its consequences in patients with CHF, current guidelines do not provide clear direction for fluid management. Using a rat model of CHF, we investigated altering drinking behaviors and explored fluid management strategies. CHF was induced by ligating the left anterior descending coronary arteries in 8-week-old, male, Sprague-Dawley rats. A custom-designed drop counting and feedback control system was used to record and modulate drinking behaviors. During the first month after an induced myocardial infarction (MI), we observed that the spontaneous per drinking volume (PDV) was significantly increased in animals with prolonged intervals between drinking episodes. In addition, there was a significant inverse correlation between the early PDV and the post-MI lifespan (r = -0.907; P < 0.001). Moreover, modulating the drinking behavior of rats with CHF to involve frequent drinking of small PDVs significantly enhanced hemodynamics and prevented cardiac remodeling, with a significant improvement in the 180-day survival rate, compared with animals allowed to drink freely (50% vs. 36%; P < 0.01). The results of dynamic PDV changes, after MI, suggest that an impaired thirst mechanism is associated with the sensing and regulating of fluid balance in rats with CHF These results suggest that increasing the drinking frequency, with small PDVs, may be beneficial to preventing progression of cardiac dysfunction in CHF.

Death and morbidity in pulmonary arterial hypertension (PAH) are often due to right ventricular (RV) failure and associated left ventricular (LV) dysfunction. We investigated regional myocardial remodeling and function as the basis for adverse ventricular-ventricular interactions in experimental chronic RV pressure overload. Two distinct animal models were studied: A rabbit model of increased RV pressure-load through progressive pulmonary artery banding A rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Regional myocardial function was assessed by speckle-tracking strain echocardiography and ventricular pressures measured by catheterization before termination. Regional RV and LV myocardium was analyzed for collagen content, apoptosis and pro-fibrotic signaling gene and protein expression. Although the RV developed more fibrosis than the LV; in both models the LV was substantially affected. In both ventricles, particularly the LV, fibrosis developed predominantly at the septal hinge-point regions in association with decreased regional and global circumferential strain, reduced global RV and LV function and up-regulation of regional transforming growth factor-β1 (TGFβ1) and apoptosis signaling. A group of PAH rats who received the TGFβ blocker SB431542 showed improved RV function and reduced regional hinge-point myocardial fibrosis. RV pressure-loading and PAH lead to biventricular TGFβ1 signaling, fibrosis and apoptosis, predominantly at the septal hinge-point regions, in association with regional myocardial dysfunction. This suggests that altered geometry and wall stress lead to adverse RV-LV interactions through the septal hinge-points to induce LV fibrosis and dysfunction.

Left ventricular diastolic dysfunction is a structural and functional condition that precedes the development of heart failure with preserved ejection fraction (HFpEF). The etiology of diastolic dysfunction includes alterations in fuel substrate metabolism that negatively impact cardiac bioenergetics, and may precipitate the eventual transition to heart failure. To date, the molecular mechanisms that regulate early changes in fuel metabolism leading to diastolic dysfunction remain unclear. In this report, we use a diet-induced obesity model in aged mice to show that inhibitory lysine acetylation of the pyruvate dehydrogenase (PDH) complex promotes energetic deficits that may contribute to the development of diastolic dysfunction in mouse hearts. Cardiomyocyte-specific deletion of the mitochondrial lysine acetylation regulatory protein GCN5L1 prevented hyperacetylation of the PDH complex subunit PDHA1, allowing aged obese mice to continue using pyruvate as a bioenergetic substrate in the heart. Our findings suggest that changes in mitochondrial protein lysine acetylation represent a key metabolic component of diastolic dysfunction that precedes the development of heart failure.

We assessed PET-CT myocardial blood flow (MBF) using N-13 ammonia, brachial flow-mediated dilation, and cardiopulmonary exercise test in five post-discarged MIS-C survivors. None of the patients (median age: 9, range: 7-18 years; 3 females; 2 males) had preexisting pediatric chronic conditions. At the follow-up visit, two patients exhibited severe perfusion defect developed in the left ventricular cavity, suggesting extensive myocardial ischemia (MBF <2.0) and one patient showed persistent mild pericardial effusion. Others two patients demonstrated endothelial dysfunction. Nevertheless, all patients had lower predicted values in the VO2peak , VO2VAT , OUES, and O2 Pulse (range: 35.2%-64.5%; 15.6%-38.2%; 1.0-1.3 L/min; 4-7 ml/beat), respectively. Our d suggested that previously health MIS-C patients had impaired MBF, endothelial dysfunction and lower cardiopulmonary capacity at follow-up analysis. Multidisciplinary further investigations should be conducted to reinforce these findings.

In patients with chronic aortic regurgitation (AR), excessive preload and afterload increase left ventricle wall stress, leading to left ventricular systolic dysfunction. Thus, the objective of the present study was to evaluate the effects of the myosin activator omecamtiv mecarbil (OM) on left ventricle wall stress in an experimental rat model of severe chronic AR. Forty adult male Wistar rats were randomized into two experimental groups: induction of AR (acute phase) by retrograde puncture (n = 34) or a sham intervention (n = 6). Rats that survived the acute phase (n = 18) were randomized into an OM group (n = 8) or a placebo group (n = 10). Equal volumes of OM (1.2 mg/kg/h) or placebo (0.9% NaCl) were continuously infused into the femoral vein over 30 min. OM significantly decreased end-systolic and end-diastolic and maximum wall stress in this experimental rat model of chronic severe AR (p < 0.001) and increased systolic performance assessed by fractional shortening and left ventricle end-systolic diameter; both p < 0.05). These effects were correlated with decreased indices of global cardiac function (cardiac output and stroke volume; p < 0.05) but were not inferior to baseline pump indices. Infusion with placebo did not affect global cardiac function but decreased end-systolic wall stress (p < 0.05) and increased systolic performance (all p < 0.001). In the sham-operated (control) group, OM decreased diastolic wall stress (p < 0.05). Based on these results, OM had a favorable effect on left ventricle wall stress in an experimental rat model of severe chronic AR.

We recently reported that mitochondrial dysfunction, characterized by increased mitochondrial permeability transition (MPT), was present in a translational swine model of heart failure with preserved ejection fraction (HFpEF). Cyclophilin D is a key component of the MPT pore, therefore, the purpose of this study was to test the efficacy of a novel cyclosporine (CsA) dosing scheme as a therapeutic alternative for HFpEF. Computed tomography (CT), two-dimensional speckle tracking two-dimensional speckle tracking (2DST), and invasive hemodynamics were used to evaluate cardiac function. CT imaging showed 14 weeks of CsA treatment caused eccentric myocardial remodeling (contrasting concentric remodeling in untreated HF animals) and elevated systemic pressures. 2DST detected left ventricular (LV) mechanics associated with systolic and diastolic dysfunction prior to the onset of significantly increased LV end diastolic pressure including: (1) decreased systolic apical rotation rate, longitudinal displacement, and longitudinal/radial/circumferential strain; (2) decreased early diastolic untwisting and longitudinal strain rate; and (3) increased late diastolic radial/circumferential mitral strain rate. LV mechanics associated with systolic and diastolic impairment was enhanced to a greater extent than seen in untreated HF animals following CsA treatment. In conclusion, CsA treatment accelerated the development of heart failure, including dilatory LV remodeling and impaired systolic and diastolic mechanics. Although our findings do not support CsA as a viable therapy for HFpEF, 2DST was effective in differentiating between progressive gradations of developing HF and detecting diastolic impairment prior to the development of overt diastolic dysfunction.

Atrial fibrosis can be estimated noninvasively by magnetic resonance imaging (MRI) using late gadolinium enhancement (LGE), but diastolic dysfunction is clinically assessed by transthoracic echocardiography (TTE), and rarely by MRI. This study aimed to evaluate well-established diastolic parameters using MRI, and validate them with TTE and left ventricular (LV) filling pressures, and to study the relationship between left atrial (LA) remodeling and parameters of diastolic function. The study retrospectively included 105 patients (53 ± 16 years, 39 females) who underwent 3D LGE MRI between 2012 and 2016. Medical charts were reviewed for the echocardiographic diastolic parameters E, A, and e' by TTE, and pressure catheterizations. E and A were measured from in-plane phase-contrast cardiac MRI images, and e' by feature-tracking, and validated with TTE. Interobserver and intraobserver variability was examined. Furthermore, LA volumes, function, and atrial LGE was correlated with diastolic parameters. Evaluation of e' in MRI had strong agreement with TTE (r = 0.75, P < 0.0001), and low interobserver and intraobserver variability. E and A by TTE showed strong agreement to MRI (r = 0.77, P = 0.001; r = 0.73, P = 0.003, for E and A, respectively). Agreement between E/e' by TTE and MRI was strong (r = 0.85, P = 0.0004), and E/e' by TTE correlated moderately to invasive pressures (r = 0.59, P = 0.03). There was a strong relationship between LA LGE and pulmonary capillary wedge pressure (r = 0.81, P = 0.01). In conclusion, diastolic parameters can be measured with good reproducibility by cardiovascular MRI. LA LGE exhibited a strong relationship with pulmonary capillary wedge pressure, an indicator of diastolic function.